Wednesday, May 29, 2013


Last week I discussed the fact that for most chemicals (i.e., those NOT identified as carcinogens) quantitative risk at any exposure including the exposure limit is NOT estimated as part of any documentation describing the toxicity of those chemicals. In the case of identified carcinogens, however, a quantitative level of risk IS estimated such that some finite risk is assigned for every exposure down to zero. The “allowable” exposure for members of the general public is often set at around 1 in 100,000 or 1 in 1,000,000 extra or additional risk of getting cancer during a lifetime of exposure at this level.   The “acceptable” level set for occupational exposures to carcinogens is typically set at exposure limits which render an estimated risk around 1 in 1,000 extra or additional risk of cancer.  The natural questions are:  Where did the one in 1,000 come from?  Why is there such a large difference between workers and the general public?  Shouldn't we be just as protective of workers as we are members of the general public?   The answers are interesting and the subject of this week’s blog.

The conventional wisdom is that the 1 in 1,000 number came out of the US Supreme Court decision on the carcinogenic risk assessment and statutory (OSHA) exposure limit for benzene.  Considering a 1 in a billion risk Justice Steven’s wrote that it “clearly could not be considered significant”.   One the other hand, he offered that a one in a thousand risk of dying from inhaling vapors containing benzene “might well” be considered significant (emphasis added).   

Hence the 1 in a 1,000 level of putative risk became the de facto standard for occupational carcinogens.   It turns out that the level of actuarial risk of death from occupational or on-the-job injury in the United States is somewhat higher.   See the table below which is perhaps 10 year old data from the US Bureau of Labor Statistics.  These are the actuarial working lifetime risk of death per thousand in various job classifications:

  • All private industry                             --              2.1
  • Manufacturing                                    --              1.6
  • Mining                                                 --            10.8
  • Construction                                       --               5.9
  • Finance                                               --               0.6
  • Commercial Fishing                            --             61
Readers who have watched "The Deadliest Catch" on TV will appreciate the last entry.

From my perspective, a putative risk at 1 in 1,000 for cancer using a linear dose response model described in my previous blogs fits in reasonably well with these actuarial risks. Other reason that folks have given to rationalize a higher risk for workers than the general public includes the fact that workers are normally healthier than individuals in the general populations which includes very old, very young and some critically and chronically ill individuals.   Another factor that is not typically stated but perhaps implied is that workers are deriving some financial benefit from their exposure and should thus bear some higher level risk.    Whatever the reason, the difference appears to be well inculcated as a societal norm at least in the US.  

The "gut check" for me is whether I would allow or advise my son or daughter to be occupationally exposed at any such an exposure limit - that is, an exposure that would present a putative risk of 1 in 1,000.    The answer to that question depends on the data and model used to make that determination.   Given a reasonable data set, model and a clear toxicological rationale by the experts, I would.   The problem is that these elements are often not present - which will be a topic included in next week's blog.

Next week's blog will be "Uncertainty is the Bane of the Risk Assessment Process".

Friday, May 24, 2013

We do not estimate Quantitative Risk for Most Chemicals

In last week’s blog I discussed the difference between calculated actuarial risk and the risk we estimate using the risk  assessment of chemicals.   I mentioned that instead of actuarial risk which is born of historical response (e.g., deaths from auto accidents) that the estimated health risk from our exposure to chemicals is not calculated in this manner and is not nearly as accurate.  Indeed, most of the time it is not calculated at all.   At that point I did not explain any further but promised to get back to you.    Well here is the further explanation.
We have tested relatively few chemicals for their ability to cause cancer (carcinogenicity).   The reason for this is that it is very expensive (millions $)  to test rats or mice for a majority of their life span by housing and exposing them to the chemical every day or most days and then killing and studying their body tissues at the end of the study.   I had a professor who told me that about half the chemicals we test for carcinogenicity come out positive.   I have not checked this as a fact but it makes sense to me.   The manner of testing is that you exposed the animals to very high doses on the high end group of the study.   This is the so call Maximum Tolerated Dose (MTD).   A dose that is so high that the animals can just barely tolerate it without dying.   Such doses especially over a lifetime can cause all kinds of reactions in the body.   Even simple irritants can cause the cells of the body to react by reproducing prematurely and in doing so they can make mistakes in the DNA synthesis and produce a cancer.  
Even though it may be quite common when we look for it, we historically treat the identified cancer causing chemicals very differently.    The assumption is that there is no dose without risk (no threshold) and therefore the smallest amount (one molecule) presents some cancer risk and two molecules presents twice this level of risk.   This is the so call linear dose response estimate.   So we have used a linear model to estimate the dose or exposure that gives an “acceptably” low level of risk (a virtually safe dose).   This risk is often the exposure that results in 1 in 1,000,000 estimated additional cancer risk for members of the general public but about 1 in 1000 for workers.   I hope to get into the reasons for this difference in “allowable risk” in the next blog but for now it’s enough to see that we estimate a quantitative level of risk for any exposure to an identified or declared carcinogen.  
Most chemicals are not considered to be carcinogens but they are known to cause some bad health effect (e.g., liver , kidney or nervous system toxicity) given high enough dose.   Historically we do not treat non-carcinogens in the same manner.   Indeed, the conventional wisdom is that there is some threshold of exposure below which NOTHING bad happens.   Here we set “acceptable” exposure as the level that did not cause a bad effect in an animal study divided by an uncertainty or a safety factor.    The critical piece here is the assumption that a threshold exists.   The way risk is estimated is that the estimated exposure (EXP)  to the chemical is compared to the allowable exposure limit  (EL) as a ratio:   EXP/EL  =  Hazard Index (HI).    If the HI is less than 1 then everyone is happy.   If it is greater than 1 then something has to be done to control the risk.   Please note that in this scheme there is NO quantitative estimate of the risk at the exposure limit or any fraction of the limit.

For many years I would argue with my colleagues in toxicology that most thresholds cannot be proven because of limitations in our methodology.   My argument was that we should estimate the quantitative level of risk for all chemicals including non-carcinogens at and below their exposure limit or the level of “acceptable” exposure.    I wrote a paper about this in 2001 with two colleagues that was largely ignored.     More recently (2009) the 'National Academy of Sciences (NAS) published the so called “Silver Book” which basically agrees with me that the distinction between carcinogens and non-carcinogens is not valid and that the quantitative level of risk should be estimated for all.   The NAS now offers all its books as free PDFs for 'download.   If you are interested in getting this book go to:
Chapter 5 is where the action is on this topic.

I will be happy to send anyone a PDF our 2001 paper if you send me an email request:

So far the occupational health community has continued to successfully ignore this issue and continues to not estimate quantitative levels of risk for non-carcinogens.
Next time I will discuss the difference between exposure limits for workers and the general public.


Tuesday, May 14, 2013

Actuarial Risk versus the Risk Estimated from Our Chemical Exposure

Actuarial Risk is very different from the risk to human health that we estimate from chemical exposure.    Indeed, actuarial risk is pretty straightforward.   It is simply the historical risk of an activity with the assumption that the present and near future will be like the past.  Let's look at the risk of traffic accidents. About 35,000 American died in traffic accidents in 2010 (the last year I could easily find with complete data).  One might predict from this that about that many would died again in 2011 and 2012.   Given a 75 year lifetime this is a lifetime risk of about 1 in 150.   In reality this risk, for a number of reasons that I will not go into, has come down steadily in the last 40 years or so.  This actual risk was about 1/65 in 1969.

This is actuarial risk and given the numbers it is easy to calculate and from year to year is pretty accurate for systems that change slowly.  Insurance companies rely heavily on this to set premiums in a effort to be competitive and to assure that they will remain profitable.

The estimated risk from our exposure to chemicals is not calculated in this manner and is not nearly as accurate. Indeed, most of the time it is not calculated at all.  But forgive me, I am getting ahead of myself. The very important topic of calculating the risk to exposure to non-carcinogenic chemical will be a matter for another blog.  Here I will talk about the calculated or estimated human risk of getting cancer from exposure to a chemical suspected to cause cancer at least in animals.   The standard manner of testing a chemical for its ability to cause cancer is to expose separate groups of animals (perhaps 20-50 rats or mice in each group) to high levels of the chemical for a majority of their lifetime (typically 2 years) with the highest dose designed to be so toxic as to be the highest dose the animals can tolerate without quickly dying from it.  This is called the Maximum Tolerated Dose (MTD) for the highest group and then perhaps 2 or 3 groups at fractions of this dose with the hope that a least the lowest dose will result in a No Observed Adverse Effect Level (NOAEL).    At the end of the study the animals are killed and surgically examined very carefully by a pathologist for any signs of cancer in their tissues.   Say that 10 out of 20 in the MTD group got a certain tumor then the response would be 50%.     Typically the lower dose groups will, as expected, give lower response rates and the NOAEL will have a response rate that is indistinguishable from control rats that were treated the same but without exposure to the chemical.  In reality the NOAEL dose would have resulted in 3-20% response if a much larger number of rats than 20-50 had been tested.

Now comes the magic.   We are not interested in an exposure that gives 10% or even 1% risk.  This is simply too high.   We want to know what the exposure is that results in a risk of 1 in a million or 1 in 100,000 for members of the general public. For workers we often look upon a much higher risk  as "not unacceptable" but we are sticking here in our example with the general public .   In order to estimate this level of risk one needs to apply a mathematical model to fit the data and do what is known as low dose extrapolation based on the model.   The problem is that there are many models that fit the known data but give very different estimated exposures for 1 in 1,000,000 risk.   As a result the estimated risk at any exposure that people might actually be exposed to can vary by a hundred or even more than a thousand fold.   The EPA has adopted a model that it uses to do this extrapolation but it can be argued that this model and indeed all the other models are arguments without data.   We simply do not know what is happening to human tissues as a result of any low exposure level nor do we know the actual risk posed at these low levels.  The risk predicted by these models at these environmentally relevant exposures are not actual risk they are putative risk.

A model-predicted risk of 1 in 1,000,000 for the pesticides in the salads we eat does not mean that one in million (between 300-350 folks in the US) will get cancer in their lifetime from eating their salad.   The number may be zero or even a negative number (i.e., protection from cancer) depending on which model one uses for low dose extrapolation.   I know it may be intriguing but I am also leaving negative risk at low dose as another topic for a future blog.  Its enough here to remember that the putative cancer risk assessment  from chemical exposure is putative and not actual risk and as such full of uncertainty.

Wednesday, May 8, 2013


Preliminary comments on blogging mechanics.

Many of the people that I most want to see this blog are on LinkedIn.   There are no auto buttons for linking to LinkedIn on Google blog so I had to learn how to find and insert some HTML code into the blog template to make that happen.    It seemed to work fine except that the process chopped off the title of the blog and it somehow killed the link to my web site while inserting a link to another unrelated web site over the text “risk assessment”.   I am not sure how to fix this but until I can fix it I will be putting the title in the first line of any subsequent blog and somewhere in there I will have my web site and this blog site spelled out.


In order to understand the risk from a chemical to human health, one needs to understand its toxicity.   That is, WHAT happens when you become overexposed to it (e.g., it damages your kidneys or lungs or brain, etc).   Indeed, every substance (even oxygen) is toxic given a high enough exposure while some chemicals are toxic at very low doses (e.g., bis-chloromethylether).   Once you know the toxicity you need to understand the level of actual human exposure to that chemical.   The simple equation is:

Risk = The integrated product of Toxicity and Exposure

You cannot even start a risk assessment without some knowledge of the toxicity of the chemical. Many folks assume that the chemicals we are exposed to have been tested for toxicity.   The fact of the matter is that in the vast majority of cases they have not.   For the most part, except for pesticides and chemicals which have proven themselves dangerous because people become frankly sick or died from exposure to them (e.g., benzene), there has been relatively little testing of their toxic effects.   Indeed, 16 year ago the Environmental Defense Fund issued a ground breaking report:  Toxic Ignorance  -   

An excerpt from that document quotes even earlier work:  “In the early 1980s, the National Academy of Sciences’ National Research Council completed a four-year study and found that 78% of the chemicals in highest-volume commercial use had not had even "minimal" toxicity testing. Thirteen years later, there has been no significant improvement.”  Well now the clock is up to almost 30 years.

This turned out to be such a powerful message in 1997 that the EPA got involved and started the High Product Volume (HPV) challenge program in which companies would volunteer to test these chemicals.   From my perspective it is safe to say that this program has been evaluated by many as being not completely successful.   I am not familiar with the details but I do know that for most of the chemicals for which I go looking today for good toxicology data in order to make some decisions about the type of adverse health effect or its potency I come up empty.   There are literally tens of thousands of chemicals in our environment, mostly from the chemicals we as a society produce and use to make our life better.  The vast majority of these have no definitive or inadequate toxicity data on them.   

There are new attempts to fill this gap from a scientific (EPA ToxCast Screen) and a regulatory perspective (European REACh program) which I hope to discuss in a future blog.   In the meantime, I have an opinion relative to the title of this blog.   My sense is that the vast majority of chemicals that we use and are exposed to in our everyday lives are safe at the exposure levels that most of us encounter.  Thus, I do not think that we should be lying awake at night worrying about our exposures.   Having said this, please note that it is simply my opinion.   It is an opinion born of a professional lifetime working in this field; however it is important to realize that my opinion is NOT a risk assessment.    Also I am also almost certain that there are some (perhaps many) chemicals and some subpopulations of people whose exposures to those chemicals are dangerous but, at this point, they remain unevaluated and thus not controlled. I think most of this happens in the workplace but some may be happening in our homes.  Suffice it to say that without the data and subsequent risk assessments, the size of these subpopulations is unknown.  In short, a lot of regulatory/political and scientific work remains to be done to identify these situations and to protect these folks.